Molecular ordering of the Fas-apoptotic pathway: The Fas/APO-1 protease Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-like cysteine proteases
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- Srinivasa M. Srinivasula
- Center for Apoptosis Research, Department of Biochemistry and Molecular Pharmacology and the Kimmel Cancer Institute, Jefferson Medical College, Philadelphia, PA 19107
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- Manzoor Ahmad
- Center for Apoptosis Research, Department of Biochemistry and Molecular Pharmacology and the Kimmel Cancer Institute, Jefferson Medical College, Philadelphia, PA 19107
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- Teresa Fernandes-Alnemri
- Center for Apoptosis Research, Department of Biochemistry and Molecular Pharmacology and the Kimmel Cancer Institute, Jefferson Medical College, Philadelphia, PA 19107
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- Gerald Litwack
- Center for Apoptosis Research, Department of Biochemistry and Molecular Pharmacology and the Kimmel Cancer Institute, Jefferson Medical College, Philadelphia, PA 19107
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- Emad S. Alnemri
- Center for Apoptosis Research, Department of Biochemistry and Molecular Pharmacology and the Kimmel Cancer Institute, Jefferson Medical College, Philadelphia, PA 19107
抄録
<jats:p>The Fas/APO-1-receptor associated cysteine protease Mch5 (MACH/FLICE) is believed to be the enzyme responsible for activating a protease cascade after Fas-receptor ligation, leading to cell death. The Fas-apoptotic pathway is potently inhibited by the cowpox serpin CrmA, suggesting that Mch5 could be the target of this serpin. Bacterial expression of proMch5 generated a mature enzyme composed of two subunits, which are derived from the precursor proenzyme by processing at Asp-227, Asp-233, Asp-391, and Asp-401. We demonstrate that recombinant Mch5 is able to process/activate all known ICE/Ced-3-like cysteine proteases and is potently inhibited by CrmA. This contrasts with the observation that Mch4, the second FADD-related cysteine protease that is also able to process/activate all known ICE/Ced-3-like cysteine proteases, is poorly inhibited by CrmA. These data suggest that Mch5 is the most upstream protease that receives the activation signal from the Fas-receptor to initiate the apoptotic protease cascade that leads to activation of ICE-like proteases (TX, ICE, and ICE-relIII), Ced-3-like proteases (CPP32, Mch2, Mch3, Mch4, and Mch6), and the ICH-1 protease. On the other hand, Mch4 could be a second upstream protease that is responsible for activation of the same protease cascade in CrmA-insensitive apoptotic pathways.</jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 93 (25), 14486-14491, 1996-12-10
Proceedings of the National Academy of Sciences
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詳細情報 詳細情報について
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- CRID
- 1361418519037203840
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- NII論文ID
- 80009405515
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- ISSN
- 10916490
- 00278424
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